The present invention relates generally to prodrugs of GABA analogs which are adapted to be administered orally, and dosage forms for administering these prodrugs of GABA analogs to reduce their toxicity.
Gamma (xe2x80x9cxcex3xe2x80x9d)-aminobutyric acid (xe2x80x9cGABAxe2x80x9d) is one of the major inhibitory transmitters in the central nervous system of mammals. GABA is not transported efficiently into the brain from the bloodstream (i.e., GABA does not effectively cross the blood-brain barrier). Consequently, brain cells provide virtually all of the GABA found in the brain (GABA is biosynthesized by decarboxylation of glutamic acid with pyridoxal phosphate).
GABA regulates neuronal excitability through binding to specific membrane proteins (i.e., GABAA receptors), which results in opening of an ion channel. The entry of chloride ion through the ion channel leads to hyperpolarization of the recipient cell, which consequently prevents transmission of nerve impulses to other cells. Low levels of GABA have been observed in individuals suffering from epileptic seizures, motion disorders (e.g., multiple sclerosis, action tremors, tardive dyskinesia), panic, anxiety, depression, alcoholism and manic behavior.
The implication of low GABA levels in a number of common disease states and/or common medical disorders has stimulated intensive interest in preparing GABA analogs, which have superior pharmaceutical properties in comparison to GABA (e.g., the ability to cross the blood brain barrier). Accordingly, a number of GABA analogs, with considerable pharmaceutical activity have been synthesized in the art (See, e.g., Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman, International Publication No. WO 92/09560; Silverman et al., International Publication No. WO 93/23383; Horwell et al., International Publication No. WO 97/29101, Horwell et al., International Publication No. WO 97/33858; Horwell et al., International Publication No. WO 97/33859; Bryans et al., International Publication No. WO 98/17627; Guglietta et al., International Publication No. WO 99/08671; Bryans et al., International Publication No. WO 99/21824; Bryans et al., International Publication No. WO 99/31057; Belliotti et al., International Publication No. WO 99/31074; Bryans et al., International Publication No. WO 99/31075; Bryans et al., International Publication No. WO 99/61424; Bryans et al., International Publication No. WO 00/15611; Bryans, International Publication No. WO 00/31020; Bryans et al., International Publication No. WO 00/50027; and Bryans et al., International Publication No. WO 02/00209).
However, many GABA analogs, including those described above exhibit poor oral absorption across the gut wall. One potential solution to the above problem is converting GABA analogs to prodrugs of GABA analogs (Bryans et al., International Publication No. WO 01/90052; U.K. Application GB 2,362,646; European Applications EP 1,201,240 and 1,178,034; Yatvin et al., U.S. Pat. No. 6,024,977; Gallop et al., U.S. patent application Ser. No. 10/171,485, entitled xe2x80x9cProdrugs of GABA Analogs, Compositions and Uses Thereofxe2x80x9d; Gallop et al International Publication No. WO 02/28881; Gallop et al, International Publication No. WO 02/28883; Gallop et al, International Publication No. WO 02/28411; Gallop et al, International Publication No. WO 02/32376; Gallop et al, International Publication No. WO 02/42414). Typically, in a prodrug, a polar functional group (e.g., a carboxylic acid, an amino group, a hydroxyl group, etc.) is masked by a promoiety, which is labile under physiological conditions. Accordingly, prodrugs are usually transported through hydrophobic biological barriers such as membranes and typically possess superior physicochemical properties in comparison to the parent drug.
Pharmacologically effective prodrugs are ideally non-toxic and are preferably selectively cleaved at the locus of drug action. Ideally, cleavage of the promoiety occurs rapidly and quantitatively with the formation of non-toxic by-products (i.e., the hydrolyzed promoiety).
Many GABA analog prodrugs exhibit unacceptable toxicity when administered orally in conventional dosage forms. In part this is due to the high doses required for many GABA analog therapy and in part because most of the therapeutic indications for GABA analogs require long-term chronic administration (i.e., administration for periods of months, years or even for the remaining lifetime of the patient). Additional problems may be caused by the chemical structure of the promoiety, which may hydrolyze to toxic metabolites (e.g., aldehydes or acids).
Accordingly, what is needed is a method for reducing toxicity when administering prodrugs of GABA analogs. Ideally, the above method is particularly effective when the promoiety hydrolyzes to provide toxic metabolites.
The present invention addresses these and other needs by providing oral dosage forms for prodrugs of GABA analogs which exhibits lower toxicity than conventional oral dosage forms of these same prodrugs. The oral dosage form of the present invention has particular utility in administering prodrugs of GABA analogs which are metabolized to form an aldehyde. In addition, the dosage forms of the present invention may be used to administer prodrugs of GABA analogs which are metabolized to form acids which deplete the body""s carnitine reserves. The present invention also provides methods for treating patients using these dosage forms.
In one aspect, the current invention comprises an oral sustained release dosage form for administering a prodrug of a GABA analog. In another aspect, the invention comprises a method of reducing toxicity of orally administered GABA analogs. The above method includes formulating the GABA analog as a prodrug, comprised of the GABA analog covalently bound to a cleavable promoiety. The GABA analog prodrug is placed in a sustained release oral dosage form and the dosage form is introduced into an intestinal lumen of a patient by having the patient swallow the dosage form. The method further includes releasing the prodrug gradually from the swallowed dosage form into the intestinal lumen of the patient over a period of hours and allowing the GABA analog to be cleaved from the promoiety after swallowing to provide a therapeutic concentration of the GABA analog in the blood plasma of the patient. When following this method, the toxicity of the prodrug of the GABA analog is less than a toxicity of an equivalent dose of the prodrug administered from an immediate release oral dosage form. In one preferred embodiment, the prodrug is metabolized to form an aldehyde (e.g., formaldehyde). In another embodiment, the prodrug is metabolized to form an acid which depletes the body""s carnitine reserves, (e.g., pivalic acid).
Preferably, the prodrug is released from the dosage form over a period of at least about 6 hours, more preferably, over a period of at least about 8 hours, and most preferably, over a period of at least about 12 hours. Further, the dosage form preferably releases from 0 to 20% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrug in 2 to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours and greater than 75% of the prodrug in 5 to 18 hours.
In a preferred embodiment, the current invention provides an oral dosage form of a prodrug of a GABA analog, wherein the dosage form, upon swallowing, provides a curve of concentration of the GABA analog in the plasma over time, the curve having an area under the curve (AUC) which is proportional to the dose of GABA analog administered, and preferably, also has a maximum concentration Cmax that is proportional to the dose of GABA analog administered. In one embodiment, the Cmax is less than 75%, and is preferably less than 60%, of the Cmax obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form. Preferably, the AUC is at least 50% of the AUC obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form((more preferably, at least 75% of the AUC obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form) and most preferably, substantially the same as, the AUC obtained from administering an equivalent dose of the prodrug from an immediate release oral dosage form).
The oral sustained release dosage forms of the present invention can take any form as long as the release characteristics and pharmacokinetic profiles above are satisfied. For example, the dosage form can be in the form of an osmotic dosage form, a prodrug-releasing polymer, prodrug-releasing tiny timed-release pills, prodrug-releasing lipids, prodrug-releasing waxes and/or prodrug releasing beads.
The dosage forms and administration methods of the present invention may be useful for treating or preventing epilepsy, depression, anxiety, psychosis, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, panic, pain (especially, neuropathic pain and muscular and skeletal pain), inflammatory disease (i.e., arthritis), insomnia, gastrointestinal disorders or ethanol withdrawal syndrome.